As a result of the extensive research in the discovery of antiviral drugs, 43 antiviral drugs are currently approved worldwide for clinical use. However, most of them target the viral DNA polymerases. Such bias is likely due to the HSV-1 DNA polymerase being the first target ever identified for antiviral drugs. The second target discovered were the viral proteases, which are required for virion maturation. More recently, significant efforts have been placed in developing drugs that target other viral proteins. A major emphasis is on drugs that inhibit viral infectivity, wherein the drugs would block the very first events in the viral infection process. The first successful inhibitor of infectivity was T-20 or fuzeon, a peptidic inhibitor of the rearrangements of the HIV fusion proteins. This drug is clinically used, but only in combination therapies. Moreover, the drug has already selected for resistance. More recently, the interaction between the HIV glycoproteins and their cellular receptors or coreceptors has also been targeted (e.g., vicriviroc-SCH 417690, TAK-779, PRO-140, UK-427,857, GW873140 and AMD887, which all target the CCR5 coreceptor, or AMD3100 and AMD070, which target the CXCR4 coreceptor). However, all these inhibitors of infectivity suffer from significant drawbacks. For example, the peptide inhibitors have poor bioavailability and stability. Thus, they must be prepared shortly before use and can only be used by parental administration. The inhibitors of coreceptor binding have narrow specificities (such as only CCR5 or CXCR4-trophic viruses). Moreover, the inhibitors of receptor binding can also block the activities of important cellular receptors. Therefore, significant efforts are still invested in developing novel inhibitors of viral fusion that can overcome such limitations.
Current inhibitors of viral fusion target interactions between viral and cellular proteins. Indeed, all antiviral drugs have been traditionally developed to target viral proteins, which ensures specificity and safety. This is a time-tested and proven concept that has led to the development of the 43 antiviral drugs in clinical use and other drugs currently under development. Unfortunately, this approach has several limitations. Drugs that target viral proteins (directly or indirectly) promptly select for resistance. For example, this has already happened with fuzeon and even with the inhibitors of CCR5-gp41 interactions. The number of potential viral targets is also limited for viruses with small genomes, such as human papillomavirus. This approach is not conducive to the prompt development of drugs against newly identified viral pathogens either, as the proteins encoded by such pathogens must first be characterized.
As an alternative to the traditional approach, the possibility of developing antiviral drugs targeting cellular proteins has recently been investigated. This approach provides several potential benefits. Inhibition of cellular proteins required for multiple viral functions could minimize the selection for resistance, for example, and a number of cellular proteins are required for replication of the viruses with the smallest genomes. Furthermore, many cellular proteins are required for replication of even distantly related viruses. Thus, drugs targeting cellular proteins could be used against a novel pathogen even before its proteins are fully characterized. However, targeting cellular proteins could also lead to unwanted negative side-effects, as such targets are commonly expressed in many uninfected cells.